Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
  • C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
  • C07C1/325—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a metal atom
  • C07C1/327—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a metal atom the hetero-atom being an aluminium atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
  • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

• 260/239 B 260/247.5 R, 260/268 TR, 260/293.62, 260/326.8l, 260/570.5 CA, 260/570.8 TC, 260/618 R, 260/668 F Int. Cl. ..C09b 29/12 Field of Search ..260/240 TC, 571, 570.8 TC
• This invention is directed to new chemical com- 5 prefer to effect condensation between a propargyl pounds which are derivatives of dibenzo[a,d]-5H- metal halide of the formula cycloheptene; to their preparation from readily availain ble starting materials; and to their utilization, particu- (HC C CHZX M larly as therapeutic agents.
• X is a halogen
• M is a metal
• n is equal to the new chemlcal compounds.
• the new chemlcal compounds may be represented valence of M, and the compound 5-oxo-dibenzo[a,d]
• the starting material 5-oxo-dibenzo[a,d]cycloheptene may be prepared in accordance with procedures described in Cesk. Farm., Volume 11, pages 3 to 7 wherein R and R are each selected from the group which consists of alkyl or hydroxyalkyl or wherein 1 1962), or in accordance with procedures described in .lourn. Med. Chem., Volume 8, (6) page 886 (1965).
• a (W) hydroxyalkyl radicals, represented by R and/or R are The central compound on this flow sheet is the startpreferably lower alkyl radicals. ing material 5-oxo-dibenzo[a,d]cycloheptene of for- When R and/or R represent hydroxyalkyl radicals mula this may advantageously be an w-hydroxyalkyl radical, A notably fi-hydroxyethyl.
• the new products are marked by the Roman numeral I. may constitute a portion is preferably a heterocycle of In this flow sheet'the reagents utilized in the steps of the from four to seven members. Thus, this heterocycle process are indicated alongside the arrows.
• cycloheptene derivatives in the first step thereof,
• compound II is treated, preferably at the boiling point, in a mixture of ethanol and a solvent which increases the reaction velocity, such as a cyclic ether oxide, for example dioxane or tetrahydrofuran, with a suitable amine and a source of formaldehyde.
• a solvent which increases the reaction velocity such as a cyclic ether oxide, for example dioxane or tetrahydrofuran
• the reaction is preferably carried out in the presence of catalytic amounts of a copper compound.
• salts and oxides of copper for example cupric acetate, basic cupric acetate, cupric bromide, cupric chloride, cupric ammonium chloride, cupric formate, cupric nitrate, cupric oxide, cupric sulfate, cupric p-toluene sulfonate, cuprous acetate, cuprous bromide, cuprous chloride, cuprous cyanide, cuprous iodide, cuprous oxide, cuprous thiocyanate, and other copper compounds.
• Our new chemical compounds of formula I have pharmacological properties which make them valuable in therapy. In particular, they are active on the central nervous system and in the cariovascular system.
• Their acid addition salts especially those with pharmacologically acceptable acids, possess the same therapeutic properties as the bases, and are useful as therapeutic agents.
• Such salts may be mentioned the oxalates, maleates and hydrochlorides.
• the resulting product is then dissolved in a minimum amount of chloroform and subjected to chromatography on basic alumina and then eluted with ether.
• the ether is removed from the resulting ethereal solution, followed by redissolving the product in a warm mixture containing equal parts of ethanol and isopropanol.
• the solution is subjected to treatment with animal charcoal and filtered.
• the product, the title compound crystallizes slowly. It is removed by centrifugal action and dried. Its melting point is 90C. (Kofler).
• the mixture is refluxed for 3 hours. It is then diluted by addition of 5 volumes of water. Sufficient ammonia is added to render the solution alkaline in reaction. This is followed by extraction with ether, drying over sodium sulfate, and removal of the solvent at a reduced pressure less than atmospheric, i.e. under vacuum.
• the title compound is obtained upon crystallization from cyclohexane. Melting point, 138C.
• the mixture is heated at reflux for 3 hours. It is then diluted by the addition of 5 volumes of water, followed by the addition of an excess of acetic acid. It is then extracted with ether and the aqueous phase is rendered alkaline by the addition of ammonia. This is followed by extraction with ether, drying over sodium sulfate, and removal of the solvent by evaporation at a reduced pressure, less than atmospheric, ie under vacuum.
• This new compound was characterized by its dimaleate salt, which is soluble in ethanol and has a melting point of 176C. Analysis confirmed the empiric fomlula CmHmNzOg.
• AU-2l76 administered orally at a dosage of milligrams per kilogram of body weight prolongs the motor excitation caused in rats by amphetamine (administered at a dosage of 4 milligrams per kilogram intraperitoneally). Furthermore, AU-2 l 76 (the hydrochloride salt) administered to rats and mice at dosages of 5 milligrams per kilogram of body weight intraperitoneally, exerts an antinociceptive action vis-avis a chemical stimulus: phenyl benzoquinone.
• AU-2l76 (the hydrochloride salt) at concentrations of 5 X 10" to 10* gram exerts in vitro a guanidine-like action on the isolated auricle of the guinea pig or rabbit, which animals were electrically excited, and prolongation of the refractory'period also is observed.
• novel compounds 1, possessing therapeutic action are of low toxicity, and the ratio of activity to toxicity presents a satisfactory margin.
• the DL of AU-2l73 in mice is 222 milligrams per kilogram of body weight when administered intraperitoneally, and 2,600 milligrams per kilogram of body weight when administered orally.
• That of AU-2l76 is 158.3 milligrams per kilogram of body weight when intraperitoneally administered, and 956 milligrams peer kilogram of body weight when administered orally.
• AU-2l76 in the form of its hydrochloride salt in a daily dosage of milligrams per kilogram of body weight for 30 days in young rats does not prevent normal growth and does not modify the hematological constants.
• the new therapeutic agents may be administered orally or parenterally, the active agent being either in non-toxic salt form or in base form.
• the compound of formula 1 may be prepared in the usual way for administration with the usual vehicles and excipients suitable for these modes of administration.
• suitable pharmaceutical formulations include tablets, dragees, gelatin capsules, solutions in ampoules and injectable solutions which may be in ampoules.
• the amount of active agent administered as a unit dose may vary from 5 to 50 milligrams, and there may be administered to the patient one or several such doses daily.
• the average daily dose will ordinarily vary from 0.1 milligram to milligrams per kilogram of body weight of the patient.
• This preparation will yield 100,000 gelatin capsules each containing 200 milligrams of powder.
• the mixture is thoroughly mixed and placed in capsules of appropriate size.
• the AU-2l76 in the form of its hydrochloride salt, is dissolved in warm water, filtered and placed in am- I poules of 5 milliliters content. They are then sterilized as by aseptic filtration or by autoclaving.
• N- alkyl-piperazine is N-lower alkyl piperazine.
• An acid addition salt of 5-(4-dimethylamino-2- butynel-ylidene )dibenzo[a,d]-5H-cycloheptene selected from the oxalate, maleate and hydrochloride acid addition salts, as claimed in claim 1.
• An acid addition salt of 5-(4-piperidino-2-butynel-ylidene )dibenzo[a,d]-5l-l-cycloheptene selected from the oxalate, maleate and hydrochloride acid addition salts, as claimed in claim 1.
• An acid addition salt of 5-(4-diethylamino-2-butyne-l-ylidene )dibenzo[a,d]-5H-cycloheptene selected from the oxalate, maleate and hydrochloride acid addition salts, as claimed in claim 1.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Citations (4)

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• 1969
  • 1969-05-20 FR FR696916251A patent/FR2005201B1/fr not_active Expired
• 1970
  • 1970-05-04 BE BE749928D patent/BE749928A/fr unknown
  • 1970-05-04 GB GB1289273D patent/GB1289273A/en not_active Expired
  • 1970-05-05 CH CH672470A patent/CH526509A/fr not_active IP Right Cessation
  • 1970-05-06 ZA ZA703057A patent/ZA703057B/xx unknown
  • 1970-05-16 DE DE19702024045 patent/DE2024045A1/de active Pending
  • 1970-05-19 CA CA083,406*7A patent/CA955249A/en not_active Expired
  • 1970-05-19 ES ES379814A patent/ES379814A1/es not_active Expired
  • 1970-05-20 SE SE06906/70A patent/SE367183B/xx unknown
  • 1970-05-20 DK DK257870AA patent/DK124123B/da unknown
  • 1970-05-20 NL NL707007300A patent/NL143216B/xx unknown
  • 1970-05-20 US US00039148A patent/US3723420A/en not_active Expired - Lifetime

Patent Citations (4)

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